DNA mismatch repair preferentially protects genes from mutation.
DNA mismatch repair preferentially protects genes from mutation.
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DOI：
10.1101/gr.219303.116
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发表时间：
2018-01
期刊：
影响因子：
7
通讯作者：
Harberd NP
中科院分区：
文献类型：
--
作者：
Belfield EJ;Ding ZJ;Jamieson FJC;Visscher AM;Zheng SJ;Mithani A;Harberd NP
突变是遗传变异的来源，也是生物进化的动力。许多突变最初是由于DNA复制错误而出现的。这些错误随后逃避细胞DNA修复的校正，例如，通过众所周知的DNA错配修复（MMR）机制。在这里，我们确定MMR对突变的全基因组影响。我们首先确定了近9000个突变积累超过五代在8个MMR缺陷突变积累（MA）线的模式植物物种，拟南芥。然后，我们表明，MMR缺陷大大增加了小规模插入和缺失（indels）和单核苷酸变异（SNV）突变的频率。大多数插入缺失涉及A或T核苷酸，并且优先出现在均聚（多聚A或多聚T）基因组片段中。此外，我们发现，在均聚物的拉伸发生的插入缺失的可能性是密切相关的拉伸长度，这种关系会导致在特定的均聚物的拉伸区域的局部突变率。对于SNVs，我们发现MMR缺陷既增加了它们的频率，又改变了它们的分子突变谱，导致具有正常MMR功能的生物体的GC到AT偏倚特征的进一步增强。我们最终的全基因组分析表明，MMR缺陷不成比例地增加了基因中的SNV数量，而不是基因组的非基因区域。后一种观察结果表明，MMR优先保护基因免受突变，并对理解自然选择和人类肿瘤生长过程中基因组的进化具有重要意义。
Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana. We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth.
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影响因子：
5.3
作者：
Marinus, Martin G.
通讯作者：
Marinus, Martin G.
从头响应的拟南芥突变和表述的环境响应式全基因组的积累。
影响因子：
7
作者：
Jiang C;Mithani A;Belfield EJ;Mott R;Hurst LD;Harberd NP
通讯作者：
Harberd NP
DOI：
10.1016/j.cub.2011.07.002
发表时间：
2011-08-23
期刊：
Current biology : CB
影响因子：
--
作者：
Jiang C;Mithani A;Gan X;Belfield EJ;Klingler JP;Zhu JK;Ragoussis J;Mott R;Harberd NP
通讯作者：
Harberd NP
DOI：
10.1073/pnas.1210309109
发表时间：
2012-10-09
影响因子：
11.1
作者：
Lee, Heewook;Popodi, Ellen;Foster, Patricia L.
通讯作者：
Foster, Patricia L.
影响因子：
3.3
作者：
Rutter, Matthew T.;Roles, Angela;Fenster, Charles B.
通讯作者：
Fenster, Charles B.